The present invention relates to a new process for the preparation of optically enriched substituted esters of 3-phenyl-propanoic acids and substituted 3-phenyl-propanoic acids.
Yasuo Kato et. al. have shown that incubation of xcex1-benzyloxycarboxylic esters with grown cells of the bacterium Corynebacterium equi afforded chiral esters via asymmetric hydrolysis (Tetrahedron Letters, Vol. 28, No.12, 1303-1306, 1987).
Japanese Patent Application No. 61-208680 describes methods for the production of optically active xcex1-hydroxycarboxylic acid derivatives by the use of bacteria belonging to the genus Corynebacterium. In the patent application processes are described converting racemic esters (2 g/l) in culture solutions (where the microbe is capable of growing) during 24 to 65 h of shake culturing.
However, according to K. Faber in xe2x80x9cBiotransformations in Organic Chemsitryxe2x80x9d, 4th Ed., Springer Veriag 1999, p. 10, the usage of a growing cell culture has a number of disadvantages vs. isolated enzymes, such as more difficult process control, the handling of large biomass in a chemical plant, and more by-product formation.
Japanese Patent Application No. 63-107536 describes the use of a few lipases for the production of optically active 2-hydroxycarboxylic acids and esters.
Jean-Marc Ricca et al. found that xcex1-Chymotrypsin suspended in organic solvents was stereoselective with respect to the hydrolysis of L-amino acid derivatives, but no stereoselectivity was observed when xcex1-hydroxy esters were used as substrates (J. Chem. Soc. Perkin Trans., Vol. 1, 1225-1233, 1993).
David Haigh et al. showed that a Rhizopus delemar lipase catalysed hydrolysis of methyl 3-[4-[2-[N-(benzoxazolyl)-N-methylamino]ethoxy]-phenyl]-2-methoxypropanoate affords the (R)-(+) and (S)-(xe2x88x92) isomers in  greater than 84% enantiomeric excess. (Bioorganic and Medicinal Chemistry vol. 7, 821-830, 1999).
However, to achieve such optical purity for the (S)-acid, double enzymatic resolution was necessary: The (S)-acid was isolated from the initial enzymatic hydrolysis, re-esterified, and enzymatically rehydrolysed.
As described by Collins Sheldrake Crosby (Chirality in Industry, 1992 section 1.3.1) it is a big advantage for large-scale production to process a minimum of material. To be able to do this the chiral purification needs to be performed as early as possible in a synthetic route. This is the opposite of what is seen in the Haigh reference but in line with the process described in this patent application. The overall process cost as e.g. environmental cost (less waste is generated), operating costs and material cost are in general lower for processes where the chiral separation is performed early in the synthesis as seen for the present invention.
It has recently been shown, that xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids have hypolipidemic and antihyperglycemic uses (WO 99/19313).
The synthesis of these compounds involves several steps to achieve the pure enantiomeric form of the compounds, which show pharmacological activity.
WO 00/26200 discloses the synthesis of optical enriched xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids and esters related to the compounds mentioned in WO 99/19313.
The object of the present invention is therefore to provide a new process involving an enzymatic resolution step for the preparation of optically enriched substituted esters of 3-phenyl-propanoic acids and substituted 3-phenyl-propanoic acids which process is adaptable to large scale manufacture, provides good yields and high purity and reduces the cost of manufacture as e.g. environmental cost (less waste is generated).
The present invention relates to a process comprising hydrolysis or trans-esterification of one of the two enantiomeric forms of a racemic or enantiomerically enriched ester of formula I or IV by a higher rate than the other by an enzyme to give an ester (II) and an acid (III) or two different esters (V) and (VI) with different R groups both with increased enantiomeric purity and an esterification process of a racemic or enantiomerically enriched acid (VII) by an enzyme to give an ester (IX) and an acid (VIII) both with increased enantiomeric purity.
The process can be used to synthesise important building blocks for the preparation of compounds active at the Peroxisome Proliferator-Activated Receptors (PPAR) like the ones described in WO 99/19313 and in Haigh et al. (Bioorganic and Medicinal Chemistry vol. 7. 821-830. 1999).